Human immunodeficiency virus type 1 induces 1-beta-D-arabinofuranosylcytosine resistance in human H9 cell line.

K Yusa,T Oh-Hara,S Tsukahara,T Tsuruo

doi:10.1016/s0021-9258(18)41861-3

K Yusa, T Oh-Hara + Show 2 more

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https://doi.org/10.1016/s0021-9258(18)41861-3

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Abstract

We have found that chronically HIV-1(IIIB)-infected H9 cells showed 21-fold resistance to 1-beta-D-arabinofuranosylcytosine (ARA-C) compared with uninfected H9 cells. In the infected H9 cells, a 37% increase of dCTP pool and a 34% increase of dATP were observed, and no alteration of dTTP and dGTP was observed, compared with the uninfected H9 cells. A marked decrease of ARA-CTP generation was observed in the infected H9 cells after 3-h incubation with 0.1-10 microM ARA-C. The level of deoxycytidine kinase activity with ARA-C as substrate was similar in both the infected and the uninfected cells; however, a 37-fold increase of cytidine deaminase activity was observed in the infected H9 cells. These results indicate that the induction of cytidine deaminase activity by HIV-1(IIIB) infection conferred ARA-C resistance to H9 cells. This conclusion was supported by the observation that a marked reversal of ARA-C resistance in the infected H9 cells occurred after treatment with the inhibitor of cytidine deaminase, 3,4,5,6-tetrahydrouridine. The understanding of these cellular alterations in drug sensitivity may facilitate the development of effective therapeutic strategies against HIV-1-infected cells.

Highlights

From the $Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Zkebukuro, Toshima-ku, Tokyo 170, Japan andthe SZnstituteof Applied Microbiology,University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113, Japan
We have found that chronicaHllyIV-l(I1IB)-infected sider HIV-1-infected cells as another chemotherapeutic tar
It is expected that alteration of drug sensitivity in chronfuranosylcytosine(ARA-C) compared with uninfected ically HIV-1-infected cells gives us useful information for H9 cells

Summary

Introduction

From the $Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Zkebukuro, Toshima-ku, Tokyo 170, Japan andthe SZnstituteof Applied Microbiology,University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113, Japan. These results indicate that the with pyrimidine metabolism occurred as a result of HIV-1 inductionof cytidine deaminase activity byHIV- infection in the host cells. Cytotoxicity of Reagents-The cytotoxic activity of the drug was agents have no specific cytotoxic effect on the HIV-1-infected cells.

Results

Conclusion